126 research outputs found
Új androsztán- és ösztránvázas heterociklusok szintézise = Synthesis of novel heterocycles in the androstane and estrane series
A támogatott időszakban szteránvázas O-, N- és/vagy P-atomokat tartalmazó heterociklusos származékok szintézisét végeztük el. Androszt-5-én váz D-gyűrűjéhez kondenzált arilpirazolinokat és izoxazolidineket állítottunk elő intramolekuláris 1,3-dipoláris cikloaddícióval. Értelmeztük a reakciók mechanizmusát és sztereoszelektivitását. Az előállított vegyületek számos képviselője jelentős mértékű in vitro citosztatikus aktivitást mutatott különböző rosszindulatú ráksejt vonalakon. Spirociklusos és kondenzált dioxafoszforinánok szintézisét valósítottuk meg az ösztron és a 4-androsztén sorban. NMR-spektroszkópia segítségével tanulmányoztuk a P-tartalmú hattagú heterogyűrűk oldatbeli konformációját. Új típusú izokinuklidin származékokat állítottunk elő ösztránvázas kiindulási anyagból, melynek során egyedi, az irodalomban még nem ismert reakciótípust ismertünk fel. Androsztén- és ösztránvázas triazolok és tetrazolok szintézisét végeztük el intermolekuláris Cu(I)-katalizált azid-alkin cikloaddícióval. Néhány vegyület közepes, illetve jó sejtosztódás-gátlást mutatott különböző ráksejt vonalakon. | During the supported period the syntheses of O-, N- and/or P-containing steroidal heterocyclic derivatives were carried out. Arylpyrazolines and isoxazolidines in the androst-5-ene series were prepared by 1,3-dipolar cycloaddition. The mechanism and stereoselectivity of the reactions were elucidated. Several compounds exerted marked in vitro antiproliferative activity on different malignant human cell lines. Spirocyclic and condensed dioxaphosphorinanes in the estrone and androst-4-ene series were also synthetized. The stereostructures of the six-membered P-hetero ring in solution were investigated by NMR methods. Novel types of isoquinuclidine derivatives in the estrone series were obtained, during which a unique reaction-type was recognized. The synthesis of novel triazoles and terazoles were carried out in the andostene and estrone series using Cu(I)-catalyzed azide-alkyne cycloaddition. Numerous compounds displayed moderate or good cell-growth inhibition
Szteránvázas vegyületek kutatása = Research of steroids
A szteránváz D-gyűrűjéhez kondenzált heterociklusok farmakológiailag jelentős vegyületek. A beszámolási időszakban az androszt-5-én vázhoz 17?-helyzetben kondenzált, két heteroatomot tartalmazó ciklusokat építettünk ki. Az N-fenil-, és az N-szubsztituált-fenil-2-oxazolidonokat a szteránvázhoz fűződő ?,?-haloalkil-N-ariluretánok alkalikus közegű szolvolízisével végeztük. A folyamat egy (N-5) szimbólummal jellemezhető szomszédcsoport részvétel. A 21-hidroximetilidén-pregn-5-én-20-on fenilhidrazinnal és annak szubsztituált származékaival végzett átalakítása két regioizomer N-fenil-pirazolhoz vezet. Arilpirazolin és izoxazolidin származékok előállítását 1,3-dipoláris cikloaddicióval sikerült megvalósítani az androszt-5-én sorban. A folyamat mechanizmusát és sztereoszelektivitását számításokkal sikerült alátámasztani. A 13?-ösztron sorban endo-, és exo-ciklusos ketonok kialakítását sikerült megvalósítani, melyek nitriliminnel végzett 1,3-dipoláris cikloaddícója regioizomer pirazolinokhoz vezetett. Az elállított vegyületek jelentős része jelentős antiproliferativ hatásúnak bizonyult. | Steroids bearing heterocycles attached to the D-ring of the steroid nucleus have been of pharmaceutical interest. During the supported period we carried out synthesis of steroidal two heteroatom-containing heterocycles at position 17? of androst-5-en-3?-ol. For the synthesis of the N-phenyl-, and N-(substituted-phenyl)-2-oxazolidone ring we chose cyclization of the steroidal ?,?-haloalkyl-N-arylurethanes in alkaline media. The cyclization takes place with (N-5) neighboring group participation. The reaction of 21-hydroxymethylidenepregn-5-en-20-one with phenylhydrazine, or p-substituted phenylhydrazines affords two regioisomer steroidal N-phenylpyrazolyl derivatives. Arylpyrazolynes and isoxazolidines in the androst-5-ene series were prepared by 1,3-dipolar cycloaddition. The mechanism and stereoselectivity of the reactions were elucidated. Effective syntheses of endo- and exocyclic ?,?-unsaturated ketones were carried out in the 13?-estrone series. The 1,3-dipolar cycloadditions of 15,16-unsaturated ketones with nitrilimines stereoselectively furnished two regioisomers of new condensed pyrazolynes. Several compounds exerted marked in vitro antiproliferative activity on different malignant human cell lines
Microwave-Assisted Synthesis, Proton Dissociation Processes, and Anticancer Evaluation of Novel D-Ring-Fused Steroidal 5-Amino-1-Arylpyrazoles
Effects stepwise terminal NH2-methylation of estronesalicylaldehyde-thiosemicarbazone and copper coordination, solution speciation, anticancer activity and redox activity
Szteránvázas vegyületek szintézise = Synthesis of Steroid Compounds
Az érdeklődésünk 2003-2005 között a cisz C/D gyűrűs 3-metoxi-, illetve a 3-benziloxi-ösztra-17-on származékok felé fordult. A kívánt 13α-D-szeko-ösztron-aldehid előállítására a legjobbnak a 16-jódmetil származékok bizonyultak, amelyek a kívánt 13α-szeko-ösztron-aldehiddé voltak alakíthatók. - Az aldehid csoport, valamint az olefin oldallánc lehetőséget adott egy Prins típusú ciklizációra. Ennek eredményeként a hattagú D-gyűrűs 3-metoxi-, illetve 3-benziloxi-D-homo-ösztronhoz jutottunk. - A 13β-D-szeko-ösztron-aldehid Grignard reakcióval, majd az azt követő intramolekulás Heck reakcióval hét-, nyolc-, illetve kilenctagú D-gyűrűt tartalmazó ösztron származékokhoz vezetett. - A 13α-, és a 13β-D-szeko-ösztron-aldehidek intramolekulás reakcióval gyűrűs nitronokká alakultak, amelyek N-fenil-maleinimiddel 1,3-dipoláros cikloaddícióval halogént tartalmazó D-homo-ösztron heterociklusokhoz vezettek. -Egy 9,13-áthidalt D-szeko-ösztron alkaloid típushoz jutottunk a 13β-szeko-ösztron-aldehid anilinnel, és szubsztituált anilinekkel, Lewis-sav jelenlétében végzett reakciójával. Az új D-szeko-ösztron-izokinuklidin keletkezése1,5-hidrid-ion vándorlással értelmezhető. - Új utat találtunk a transz-3β-hidroxi-16,17-szeko-pregna-5,17(20)-dién-16-al előállítására. Az így nyert szeko-szteroidban a formil csoport és a telítetlen oldallánc alkalmassá teszi a szteránvázhoz kondenzált heterociklusok kialakítását. | During the research period 2003-2005 we were interested in compounds with an inverted configuration at C-13, i.e. derivatives of 13α-estrane-17-on-3-ethers containing a cis junction of rings C and D. With the aim of preparing the 13α-D-seco-estrone aldehyde, the 16-iodomethyl derivatives were the starting materials for the fragmentation. - The presence of the olefinic moiety and the formyl group makes the molecules suitable for intramolecular Prins-type reaction. The result is the 3-methoxy-, and 3-benzyloxyestrone containing a six-membered ring D. - A new type of steroids with seven-, eight-, or nine-membered D-ring have been synthesized from 13β-D-seco-estrone aldehyde derivative by a Grignard and an intramolecular Heck reaction. - Starting from the 13α-, and 13β-D-seco-estrone aldehyde by 1,3-dipolar cycloaddition reactions with N-phenylmaleinimide stereoselectively furnished halogen-containing condensed heterocyclic D-homosteroids. - Unique 9,13-bridged D-seco-estrone alkaloids have been synthesized starting from 13β-seco-estrone aldehyde with aniline in the presence of Lewis acids. - A new synthetic route was developed for the preparation of trans-3β-hydroxy-16,17-seco-pregna-5,17(20)-dien-16-al. - Starting from the trans-3β-acetoxy-16,17-seco-pregna-5,17(20)-dien-16-al and using aniline with BF3.OEt2, different tetrahydroquinoline derivatives via Diels-Alder reaction were formed
Salicylaldehyde thiosemicarbazone copper complexes: impact of hybridization with estrone on cytotoxicity, solution stability and redox activity
An estrone–salicylaldehyde thiosemicarbazone hybrid (estrone–TSC) containing integrated domains was designed and synthesized with excellent yield via the condensation reaction of thiosemicarbazide and 2-formyl-estrone under optimized microwave reaction conditions. A structurally related bicyclic derivative (thn-TSC) starting from 5, 6, 7, 8-tetrahydro-1-naphtol (th-1-n) was also prepared in addition to their copper(II) complexes. The ligands have somewhat higher pKa values determined for the deprotonation of the hydroxyl group by UV-visible spectrophotometric and fluorometric titrations than the reference compound salicylaldehyde thiosemicarbazone (STSC), and are neutral at physiological pH. The novel conjugates are more lipophilic and possess higher membrane permeability than STSC based on the n-octanol/water partitioning and the parallel artificial membrane permeability assays, respectively. The isolated [Cu(estrone–TSCH−2)] and [Cu(thn-TSCH−2)] complexes were characterized by ESI-MS, UV-visible and EPR spectroscopy and a detailed solution study was performed to reveal their stoichiometry, stability and reduction by glutathione. The crystal structure of the ligand thn-TSC and its complex [Cu(thn-TSCH−1)Cl] was studied by single crystal X-ray diffraction method. The complexes are fairly stable at pH 7.4, the observed stability order is STSC < thn-TSC < estrone–TSC, and are able to oxidize glutathione readily. The novel ligands thn-TSC and estrone–TSC were found to be only moderately cytotoxic against several human cancer cell lines ; however rather low IC50 values were measured in the hormone-responsive MCF-7 breast cancer cell lines (thn-TSC: 3.7 μM, estrone–TSC: 6.4 μM). The copper(II) complexes exhibited high cytotoxicity (IC50 < 0.3–2 μM) and were considerably more cytotoxic than the respective ligands. Low level of reactive oxygen species was measured and a weak GSH depletion was observed for the complexes of thn-TSC and estrone–TSC in SUM159 breast cancer cells, thus their mechanism of action might be related to the induction of oxidative stress
Dynamics of hydroxide-ion-driven reversible autocatalytic networks
An autocatalytic reaction network is designed utilising the interplay of hydroxide concentration dependent reactions and acid–base equilibria of imine hydrolysis
Substitutional Diversity-Oriented Synthesis and In Vitro Anticancer Activity of Framework-Integrated Estradiol-Benzisoxazole Chimeras
Hybridization of steroids and other pharmacophores often modifies the bioactivity of the parent compounds, improving selectivity and side effect profile. In this study, estradiol and 3′-(un)substituted benzisoxazole moieties were combined into novel molecules by structural integration of their aromatic rings. Simple estrogen starting materials, such as estrone, estradiol and estradiol-3-methylether were used for the multistep transformations. Some of the heterocyclic derivatives were prepared from the estrane precursor by a formylation or Friedel–Crafts acylation—oximation—cyclization sequence, whereas others were obtained by a functional group interconversion strategy. The antiproliferative activities of the synthesized compounds were assessed on various human cervical, breast and prostate cancer cell lines (HeLa, MCF-7, PC3, DU-145) and non-cancerous MRC-5 fibroblast cells. Based on the primary cytotoxicity screens, the most effective cancer-selective compounds were selected, their IC50 values were determined and their apoptosis-inducing potential was evaluated by quantitative real-time PCR. Pharmacological studies revealed a strong structure–function relationship, where derivatives with a hydroxyl group on C-17 exhibited stronger anticancer activity compared to the 17-acetylated counterparts. The present study concludes that novel estradiol-benzisoxazole hybrids exert remarkable cancer cell-specific antiproliferative activity and trigger apoptosis in cancer cells
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